Shona Kalkman

Pragmatic randomized trials in drug development pose new ethical questions : A systematic review

Implementation of pragmatic design elements in drug development could bridge the evidence gap that currently exists between the knowledge we have regarding the efficacy of a drug versus its true, comparative effectiveness in real life. We performed a review of the literature to identify the ethical challenges thus far related to pragmatic trials. The three central ethical questions identified for pragmatic trials are: (i) what level of oversight should pragmatic trials require; (ii) do randomized patients face additional risks; and (iii) is a waiver of informed consent ethically defensible? Despite the fact all reviewed publications dealt with post-launch pragmatic trials, these results could serve as an important starting point for conceptualizing which challenges could potentially arise in the pre-launch setting.

The effects of under 6 hours of formalin fixation on hormone receptor and HER2 expression in invasive breast cancer: a systematic review.

OBJECTIVES A systematic review of the literature was performed to identify whether minimum formalin fixation time may be reduced for reliable immunohistochemical assessment of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). METHODS PubMed, EMBASE, and the Cochrane Library were systematically searched for studies addressing effects of brief tissue fixation (<6 hours) on the analysis of ER, PR, or HER2 expression in patients with breast cancer. RESULTS Five publications reported effects of brief fixation on ER, PR, or HER2 expression. Four studies showed similar receptor expression of short fixation compared with recommended fixation time (6-72 hours). One publication found that a minimum fixation time of 6 to 8 hours is necessary for reliable ER results. CONCLUSIONS Available data on the effect of brief fixation on receptor status are limited. However, brief fixation of very highly expressing breast cancers does not seem to alter ER, PR, and HER2 status. Nevertheless, scoring inconsistencies have been observed. Further research is required in larger study populations with more low-expressing cases for future validation.

Series: Pragmatic trials and real world evidence: Paper 4. Informed consent

The GetReal consortium of the Innovative Medicines Initiative aims to develop strategies to incorporate real-world evidence earlier into the drug life cycle to better inform health care decision makers on the comparative risks and benefits of new drugs. Pragmatic trials are currently explored as a means to generate such evidence in routine care settings. The traditional informed consent model for randomized clinical trials has been argued to pose substantial hurdles to the practicability of pragmatic trials: it would lead to recruitment difficulties, reduced generalizability of the results, and selection bias. The present article analyzes these challenges and discusses four proposed alternative informed consent models: integrated consent, targeted consent, broadcast consent, and a waiver of consent. These alternative consent models each aim at overcoming operational and methodological challenges, while still providing patients all the relevant information they need to make informed decisions. Each consent model, however, relies on different attitudes toward the principle of respect for persons and the related duty to inform patients as well as represents different views on whether the common good demands moral duties from patients. Such normative consequences of modifying consent requirements should be at least acknowledged and ought to be assessed in light of the validity of empirical claims.

Brief fixation does not affect assessment of hormone receptor expression in invasive breast carcinoma biopsies: paving the road for same-day tissue diagnostics.

In patients with invasive breast carcinoma, estrogen receptor &agr; (ER&agr;) and progesterone receptor (PR) expressions need to be assessed in core-needle biopsies (CNBs) before the start of neoadjuvant systemic treatment. Current guidelines recommend a minimum formalin fixation time of 6 hours. Considering the increasing demand for same-day diagnostics in oncology, more rapid tissue processing with shorter fixation times is required. To identify whether brief fixation (<6 h) of CNBs compared with conventionally fixed resection specimens provides for reliable immunohistochemical assessment of ER&agr; and PR expression, 78 consecutive patients diagnosed with invasive breast carcinoma were included through the same-day diagnostics programme of the UMC Utrecht. Paraffin-embedded CNBs fixed for approximately 45 minutes were retrieved. Immunohistochemistry for ER&agr; and PR was compared between the briefly fixed CNBs and conventionally fixed resection specimens. All slides were reviewed by means of consensus scoring by 2 blinded observers. Overall agreement between CNB and resections was 73/74 (98.6%) for ER&agr; (&kgr;=0.85; 95% confidence interval [CI]=0.56-1.00) and 69/75 (92.0%) for PR (&kgr;=0.81; 95% CI=0.66-0.96). For ER&agr;, positive and negative predictive values were 98.6% (95% CI=0.91-0.99) and 100.0% (95% CI=0.31-1.00), respectively. For PR, positive and negative predictive values were 100.0% (95% CI=0.91-1.00) and 76.0% (95% CI=0.54-0.90). In conclusion, analysis of hormone receptor expression in briefly fixed CNB seems comparable to results from conventionally fixed resection specimens of the same tumor.

Series: Pragmatic trials and real world evidence: Paper 3. Patient selection challenges and consequences

This paper addresses challenges of identifying, enrolling, and retaining participants in a trial conducted within a routine care setting. All patients who are potential candidates for the treatments in routine clinical practice should be considered eligible for a pragmatic trial. To ensure generalizability, the recruited sample should have a similar distribution of the treatment effect modifiers as the target population. In practice, this can be best achieved by including-within the selected sites-all patients without further selection. If relevant heterogeneity between subgroups is expected, increasing the relative proportion of the subgroup of patients in the heterogeneous trial could be considered (oversampling) or a separate trial in this subgroup can be planned. Selection will nevertheless occur. Low enrollment and loss to follow-up can introduce selection and can jeopardize validity as well as generalizability. Pragmatic trials are conducted in clinical practice rather than in a dedicated research setting, which could reduce recruitment rates. However, if a trial poses a minimal burden to the physician and the patient and routine clinical practice is maximally adhered to, the participation rate may be high and loss to follow-up will not be a specific problem for pragmatic trials.

Stakeholders’ views on the ethical challenges of pragmatic trials investigating pharmaceutical drugs

BackgroundWe explored the views of key stakeholders to identify the ethical challenges of pragmatic trials investigating pharmaceutical drugs. A secondary aim was to capture stakeholders’ attitudes towards the implementation of pragmatic trials in the drug development process.MethodsWe conducted semistructured, in-depth interviews among individuals from different key stakeholder groups (academia and independent research institutions, the pharmaceutical industry, regulators, Health Technology Assessment (HTA) agencies and patients’ organizations) through telephone or face-to-face sessions. Interviews were structured around the question “what challenges were experienced or perceived during the design, conduct and/or review of pragmatic trials.” Respondents were additionally asked about their views on implementation of pragmatic trials in the drug development process. Thematic analysis was used to identify the ethically relevant features across data sets.ResultsWe interviewed 34 stakeholders in 25 individual sessions and four group sessions. The four perceived challenges of ethical relevance were: (1) less controlled conditions creating safety concerns, (2) comparison with usual care potentially compromising clinical equipoise, (3) tailored or waivers of informed consent affecting patient autonomy, and (4) minimal interference with “real-world” practice reducing the knowledge value of trial results.ConclusionsWe identified stakeholder concerns regarding risk assessment, use of suboptimal usual care as a comparator, tailoring of informed consent procedures and ensuring the social value of pragmatic trials. These concerns increased when respondents were asked about pragmatic trials conducted before market authorization.

Brief fixation does not hamper the reliability of Ki67 analysis in breast cancer core-needle biopsies: a double-centre study

Immunohistochemical assessment of Ki67 expression in core‐needle biopsies (CNBs) is increasingly playing a role in therapeutic decision‐making for breast cancer patients. Within the framework of same‐day diagnosis of breast lesions, fixation times are markedly decreased. We therefore attempted to validate Ki67 analysis in briefly fixed breast cancer CNBs.

Survival after Perioperative Cardiopulmonary Resuscitation : Providing an Evidence Base for Ethical Management of Do-not-resuscitate Orders

Automatic suspension of do-not-resuscitate (DNR) orders during general anesthesia does not sufficiently address a patient’s right to self-determination and is a practice still observed among anesthesiologists today. To provide an evidence base for ethical management of DNR orders during anesthesia and surgery, the authors performed a systematic review of the literature to quantify the survival after perioperative cardiopulmonary resuscitation (CPR). Results show that the probability of surviving perioperative CPR ranged from 32.0 to 55.7% when measured within the first 24 h after arrest with a neurologically favorable outcome expectancy between 45.3 and 66.8% at follow-up, which suggests a viable survival of approximately 25%. Because CPR generally proves successful in less than 15% of out-of-hospital cardiac arrests, the altered outcome probabilities that the conditions in the operating room bring on warrant reevaluation of DNR orders during the perioperative period. By preoperatively communicating the evidence to patients, they can make better informed decisions while reducing the level of moral distress that anesthesiologists may experience when certain patients decide to retain their DNR orders.

Assessment of HER2 status in breast cancer biopsies is not affected by accelerated tissue processing

To establish whether core needle biopsy (CNB) specimens processed with an accelerated processing method with short fixation time can be used to determine accurately the human epidermal growth factor receptor 2 (HER2) status of breast cancer.

Pragmatic clinical trials: ethical imperatives and opportunities

Pragmatic clinical trials generate robust real-world evidence that holds great potential to better inform decision making regarding new medicines. For clinicians, patients and regulators, this evidence would preferably be available sooner rather than later. This means that, ideally, market authorization of any given medicine is accompanied by evidence obtained from a pragmatic trial. Given the operational and regulatory complexities of pragmatic trials in general, stakeholders tend to be hesitant to employ more pragmatism at the time of market approval. One prominent hurdle for the conduct of pragmatic trials is the concern that pragmatic design features conflict with ethical standards for clinical trials. To encourage timely yet responsible generation of real-world evidence through clinical trials, it is important to delineate exactly which areas, from a societal point of view, demand early pragmatic evaluations. We also urge stakeholders to recognize how the current system of trial ethics oversight already accommodates for more-pragmatic approaches, and how new ideas about their permissibility have progressed in the bioethics literature.